Silver is known to possess broad spectrum antimicrobial activity and has been incorporated in a variety of medical care products such as dressings, hydrogels, hydrocolloids, foams, creams, gels, lotions, catheters, sutures, bandages, and positioning devices. Though specifically not recognized, the antimicrobial properties of silver were known and exploited since the times of ancient Mediterranean and Asiatic cultures. References have been made to the use of silver vessels to prevent spoilage of water during storage and of silver foil or plates in the treatment of wounds and bone fractures.
Von Nageli first systematically studied the lethal effects of metals, including silver, on bacteria and other life forms and coined the term “oligodynamic effect” for the phenomenon (C. Von Nageli, Denkschriften der Schweiz Naturforsch. Ges., Vol. 33, pp 1 (1893)). Generally speaking, the oligodynamic effect is limited to solutions in which metal ion concentration is several orders of magnitude below that which would be harmful to the patient's tissue. In the case of silver, this value is about 10−6 to 10−9 molar.
A silver compound that can maintain a silver ion concentration of at least 10−9 molar can function as antimicrobial agent. The majority of known silver salts are sparingly soluble, i.e., possess very low solubility product Ksp, and thus, the silver ion concentration in solutions are generally very low. An exception is silver nitrate, which is completely ionized at all concentrations but is prone to the loss of silver ions by de-activation by surfaces contacting the solution. Despite the slow dissolution in water due to low solubility of silver salts, not all silver compounds are useful as antimicrobial agents because of silver's adverse properties. These include a short half-life, the rapid inactivation of silver by protein or compounds having thiol groups, and light- or heat-mediated discoloration.
The antimicrobial activity and action of silver was reviewed in Russell and Hugo (Prog. Medicinal Chemistry, Vol. 31, pp 351 (1994)). It is believed that the lethal activity of silver towards microbes is due to silver's multi-site attack on microbial cells. Silver ions possess high affinity for thiol, amino and carboxyl groups and oligonucleotide bases and bind irreversibly to these groups, disrupting cells normal growth cycles and killing them. Because of silver's ability to target multiple sites on cells, the risk of microbes developing resistance to silver is extremely unlikely. Therefore, silver has found widespread use as a germicidal agent. With the emergence of methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium in recent years, the focus has increasingly shifted to the use of silver as a more robust and reliable antimicrobial agent.
Many silver compounds have been found to be useful. Silver nitrate has been used in eye drops to treat neonatal eye infections. In stick form, silver nitrate has been used to treat warts and in lotions to treat lesions. Silver nitrate combined with ammonia has been used as a antimicrobial dental protective. Several other silver salts such as acetate, citrate, lactate, picrate and methylene bis naphthalene sulfonate have found use in different therapeutic compositions—eye lotions, dust powder for wounds, in astringents and antiseptic, in treating vaginal trichomonoiasis and candidiasis and in treating burns, varicose ulcers and pressure sores. Silver protein complexes have also been widely used in preparations such as creams, lotions and ointments. In creams and lotions, a sulfonamide derivative, silver sulphadiazine, has been successful in the treatment of burns and acute and chronic wounds. However, there have been reports of microbes in hospital settings developing resistance to sulphadiazine thus limiting its widespread use.
Medical devices containing silver must meet the same requirements as other antimicrobial medical devices to be commercially successful. Silver-containing devices must maintain the same aesthetic appearance and feel and provide antimicrobial function for prolonged periods. Unfortunately, most currently available devices incorporating silver compounds are only able to fulfill the requirements to some degree, i.e. they are able to provide antimicrobial effect on sustained basis but they discolor over time. A few devices are able to fulfill both requirements but are not biocompatible at effective concentrations.
Silver-containing medical devices are prone to light and heat-induced discoloration. Often these products in contacting body parts or skin cause undesirable staining. At worst, repeated staining can lead to permanent discoloration, a condition known as argyria. The light and thermal instability of these products may also cause reliability problems in the manufacture and shelf life storage. Efforts have been tried to overcome these problems, but they have been unsuccessful, due to toxicity, continued light sensitivity or other issues.
While various approaches may be somewhat successful in imparting light stability to some products, most approaches are not broadly applicable. Silver compounds that possess good light stability do not necessarily have good thermal stability, which is often useful because in manufacturing, drying steps or sterilization operations may involve high temperatures.
None of the current silver stabilization procedures are practical to implement in preparing medical devices, such as traditional dressings, with antimicrobial property such as cotton or polyester blended cotton gauzes or sponges, or other devices. For example, in treating a cotton gauze, moderate amount of salts (chlorides) may be tolerated but excess salts tend to make a gauze material stiff giving it a crispy feel. However, with only moderate amount of salts, the light protective action may not be as effective. Occlusion by polyethylene glycols may not appropriate as it could be expensive and the presence of copper salts stain the gauze yellow. In the alternative, cotton gauzes can be rendered antimicrobial with antibiotics or other chemical agents (biguanides and chlorohexidine derivatives) but they don't perform as well.
Therefore, there is a need for antimicrobial products, including traditional dressings, such as gauze products, that provide antimicrobial characteristics from the presence of silver and provide sustained release but do not discolor under light, heat and sterilization conditions, and which are relatively inexpensive and straightforward to manufacture.